The findings explain immunodeficiency in the rare syndrome and may suggest new ways to treat autoimmune diseases – ScienceDaily

A new study from UT Southwestern suggests that RNA exosomes – the cellular machines that break down old RNA molecules – play a key role in the development of B cells, which are crucial for the immune system’s ability to fight infection. The findings published in Science Immunologyexplain why patients with rare mutations in a gene that encodes this machine are often immunodeficient and may suggest new approaches to treating autoimmune diseases.

“We were quite surprised to find that this gene, whose role was well known as part of the RNA disposal system, is also crucial to a very important part of our immune system,” said study leader Nan Yang, Ph.D. . D., Professor of Immunology and Microbiology at UT Southwestern and a member of the Harold C. Simmons Center for Comprehensive Cancer.

Many patients with a rare disease associated with RNA exosome deficiency, known as trichohepatoenteric syndrome (THES), also develop B-cell immunodeficiency and experience recurrent infections. Although researchers have long known that THES is associated with mutations in genes encoding exosomes known as SKIV2L and TTC37, the molecular basis of the disease is unknown.

To better understand the role of SKIV2L in THES, Dr. Yang’s research team in the Department of Immunology and colleagues from the Primary Immunodeficiency Clinic at UTSW and the Children’s Medical Center in Dallas studied a THES patient who carries this mutation and was part of clinical trial led by Dr. Christian Vysotsky, PhD, Associate Professor of Pediatrics. In addition to the usual clinical features of THES, a multi-organ disorder with symptoms including small size at birth, insurmountable diarrhea, distinctive “wavy hair” and liver disease, this patient had very low B cell counts.

The researchers then generated mice whose SKIV2L gene was deleted in bone marrow stem cells that generated B cells. The animals also had B-cell deficiency; further research shows that B cells have never matured because a key part of their development – in which progenitor cells randomly recombine genetic material to create a diverse pool of B cells – has not occurred.

Dr. Ian explained that this appears to be related to the role of SKIV2L in RNA degradation. In a separate finding published in the same issue of Science Immunology, researchers at Columbia University showed that mutations in other components of the RNA exosome also cause B-cell deficiency. These mutations make RNA exosomes non-functional, causing cells to selectively retain RNA, especially the non-coding form that does not produce proteins. When B-cell progenitors are destroyed by excessive non-coding RNA, they cannot mature into functional B-cells.

Taken together, the findings suggest that THES can be treated with bone marrow transplantation, replacing defective B-cell progenitors that carry a genetic mutation with healthy ones. They also suggest that SKIV2L may offer a new target for combating autoimmune diseases such as lupus, in which overactive B cells play a key role. By inhibiting the activity of this gene, Dr. Yang explained, it may be possible to control the number of B cells by reducing the intensity of the autoimmune attack.

Dr. Ian is Rita K. and William P. Clements, a junior medical research scientist.

Other UTSW researchers who contributed to this study included Kuhn Young (first author), Gye Hahn, Jennifer G. Gill, Jason Y. Park, Megana N. Sate, Jotsna Gatineni, and Tracy Wright. M. Teresa de la Morena of the University of Washington also contributed.

This study was supported by grants from the National Institutes of Health (AI153576) and the Burroughs Wellcome Foundation.

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Materials provided by UT Southwest Medical Center. Note: Content can be edited for style and length.

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